6-((2-Fluoro-3-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)propyl)amino)-2,3-dihydro-1H-inden-1-one is a potent drug-like G protein-coupled receptor 119 (GPR119) agonist. It is hoped that this compound would be instrumental in probing the pharmacological potential of GPR119 agonists.Key words glucagon-like peptide-1; G protein-coupled receptor 119 agonist; glucose-dependent insulin secretagogue; gastric emptying Obesity is strongly associated with insulin resistance and can therefore be problematic in the management of type 2 diabetes mellitus (T2DM).1,2) Ironically, treatment of T2DM also targets obesity, although oral medications, such as sulfonylureas and thiazolidinediones are known to hardly achieve weight loss. Glucose-dependent insulin secretagogues, such as glucagon-like peptide-1 (GLP-1) analogs and dipeptidyl peptidase-IV (DPP-4) inhibitors have recently emerged as new agents for the treatment of T2DM.3) Although both GLP-1 analogs and DPP-4 inhibitors improve glycemic control and minimize hypoglycemia, GLP-1 analogs can produce weight loss, while DPP-4 inhibitors merely suppress body weight gain. Very recently, G protein-coupled receptor 119 (GPCR 119, or GPR119) agonists have received considerable attention as a promising therapeutics for the treatment of T2DM. 4,5) GPR119 is a membrane receptor expressed in pancreatic islet β-cells, and its activation enhances insulin secretion in glucose-dependent manner. GPR119 expression has also been detected in murine intestinal L-and K-cell lines. In fact, treatment with AR231453, a GPR119 agonist has been reported to enhance secretion of both GLP-1 and gastric inhibitory polypeptide (GIP) in glucose-challenged mice.6) It is therefore expected that GPR119 agonists would improve glucose tolerance with minimum hypoglycemia in T2DM patients and produce weight loss by reducing food intake. Based on this hypothesis, a large number of patents and publications regarding GPR119 have been disclosed and several GPR119 agonists such as APD668, 7) MBX-2982 and GSK-1292263A have been under development. 5,8) However, there are some conflicting results from the recent publication, and the high attrition rates of early-stage development also suggest that the potential of GPR119 agonists for treatment of T2DM is still elusive. 9,10) Apparently, drug-like, selective GPR119 agonists provide a useful tool for probing the physiological roles and pharmacological potential of GPR119 agonists. Recently, we reported synthesis and pharmacological profiles of a new series of GPR119 agonists having high potency.11) This series of agonists (e.g. 6, 7) feature small species difference in the in vitro potency between mouse and human, and good physical properties such as water solubility and molecular weight. Further investigation has been carried out to improve these profiles. In this communication, we are pleased to report the synthesis and pharmacological profile of a new, selective GPR119 agonist, 6-((2-fluoro-3-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) propyl) amino)...